The Huntington's disease (HD) IPS consortium, funded with ARRA support for two years, brings together leading groups in stem cell and HD research to establish whether newly created IPS cell lines show HD-related (i.e., GAG length-dependent) phenotypes. This consortium aims to capitalize on new technologies to use non-integrating approaches for reprogramming and promising phenotypes in current HD iPS lines to develop robust and validated assays for drug development for Huntington's disease (HD), a fatal neurodegenerative condition with no current treatment. Skin cells from patients with HD can be reprogrammed to pluripotency and then differentiated into specific neuronal and glial cell types, permitting investigation of the effects of the genetic lesion in the susceptible human cell types. We have worked closely together and established novel methods of generating standardized neural stem cell cultures (e.g., EZ spheres) from three HD IPS integrating lines with a wide range of GAG repeats (33, 60 and 180), which have shown a number of promising phenotypes. The current proposal will extend these studies by producing 15 additional lines using the latest non-integrating IPS technology and will apply novel differentiation and genetic tagging protocols to further optimize the system. This funding would continue the significant synergy of this very focused consortium that (i) has a strong track record of innovative HD research and of working together, (ii) is poised to continue in cutting-edge research with induced pluripotent stem (IPS) cells derived from HD patients and is committed to broad distribution of findings, protocols and IPS lines, and (iii) is partnered with a group of investigators with the gol to optimize neuron specific differentiation protocols. Continued funding will accelerate the coordinated analysis of IPS lines and leverage the complementary, synergistic skill sets that will move the field forward more rapidly than would be possible by any group alone. Our ultimate goal is to develop and validate methods and assays using >96 well format for GAG repeat length-dependent phenotypes that are amenable to high content/throughput screening methods. The proposed studies will provide an assessment of the power of iPS cell technology for modeling HD, and for drug discovery. The monogenic nature of HD and the existence of allelic series of IPSCs with a range of GAG repeat lengths confer tremendous power to model neurodegenerative disease. These cell lines will be an essential resource for academic groups and pharmaceutical companies for studying pathogenesis and for testing experimental therapeutics for HD.